Hiv Neurology.docx

Neurological manifestations of HIV

Neurological manifestations are common in HIV. Can affect any part of neuraxis. Can occur in any stage of HIV infection. Neurological involvement can be classified based on1) Pathophysiology- Directly due to HIV/Due to OIs, neoplasms, autoimmunity/Due to drugs and IRIS 2) Anatomical location- Brain/Spinal cord/Peirpheral nervous system 3) Stage at which they occur- based on CD4 count 4) Presentation- Focal/Multifocal/Diffuse

Due to HIV

OIs

Neoplasms

Immune mediated

Drugs

Others

Brain

Aseptic meningitis Acute encephalitis HAND

Tuberculosis Cryptococcosis Toxoplasmosis PML CMV Syphilis Amoebiasis Herpes (simplex and zoster) Coccidiodes immitis Histoplasma capsulatum

Primary CNS lymphoma Kaposi sarcoma

?Multiple sclerosis like disease

Efavirenz induced neuropsychiatric syndrome

Stroke

Spinal cord

Vacuolar myelopathy

Tuberculosis HTLV-1 CMV Syphilis Herpes (zoster and simplex)

Primary CNS lymphoma Kaposi sarcoma

CNS-

Myelopathy secondary to vitamin B12 def (SACD)

PNSNerves

Distal sensory CMV polyneuropathy Leprosy

GBS CIDP Mononeuritis multiplex Bell’s palsy

Stavudine, Didanosine, Lamivudine, Zalcitabine

Muscle

Myopathy

Polymyositis

Zidovudine induced myopathy

Neuropathy secondary to vitamin def

With Focal signs

Without Focal signs

Stroke Tuberculoma Cryptococcoma Toxoplasmosis PML Primary CNS lymphoma Syphilis (meningovascular) Varicella zoster Aspergilloma

HAND Aseptic meningitis Cryptococcal meningitis Tubercular meningitis CMV encephalitis Syphilis (GPI)

Acute HIV infection In 50-70% of infected patients- 3-6 weeks after primary infection Similar to other acute viral syndromes. Duration- 1-several weeks. Neurologic manifestations- Combination of virus itself and immune reaction Meningitis, encephalitis Peripheral neuropathy -GBS, Cranial neuropathy- 7th,5th,8th, 2nd Myelopathy OIs can also occur- CD4 counts may drop, CD4+ T cells dysfunction due to viral proteins/cytokines

HIV associated Neuro-cognitive disorders (HAND) Directly attributable to HIV Spectrum- asymptomatic to severe dementia Most severe form- HIV associated dementia or AIDS-dementia complex or HIV encephalopathy- AIDS defining illness Can occur even in setting of ART and normal CD4 count Pathogenesis- HIV infection of CNS macrophages or glial cells or secondary to toxic cytokines Patients with E4 apoallele of ApoE are at increased risk Clinical staging- Frascati criteria Stage Asymptomatic Mild neurocognitive disorder HIV associated dementia

Neurocognitive status 1 SD below mean in 2 cognitive domains 1 SD below mean in 2 cognitive domains 2 SD below mean in 2 cognitive domains

Functional status No impairment in ADL Impairments in ADL Notable impairment in ADL

HIV associated dementiaMost severe form of HAND- initial AIDS defining illness in 3% and eventually develops in 25 % of untreated patients Late complication but can occur even with CD4 > 350 Clinical featuresSlowly progressive over months Major feature is dementia includes- difficulty in concentrating, forgetfulness, reading difficulty, difficulty performing complex tasks Subcortical type of dementia- mainly short term memory loss with executive dysfunction, no aphasia, apraxia, agnosia. Behavioral changes- apathy, irritability, lack of initiative, may progress to vegetative state Motor symptoms- Unsteady gait, poor balance, tremor, increased tone and DTRs Bowel and bladder incontinence in late stages

DiagnosisNo specific criteria Must be differentiated form other CNS diseases CT/MRI- Atrophy, T2 hyperintense lesions in periventricular areas on MRI CSF- Increase in protein, mononuclear pleocytosis, HIV RNA can be detected (not specific) TreatmentcART Neuroleptic sensitivity- therefore these drugs must be avoided.

Toxoplasmosis Etiologic agent- Toxoplasma gondii Late complication- when CD4 < 200 Reactivation of latent tissue cysts- 10 times more common in patients anti-toxoplasma antibodies (patient with HIV should be screened for IgG antibodies at initial workup) Clinical features due to- Direct invasion causing necrotizing encephalitis and secondary effectsvasculitis, hemorrhage, edema

Clinical featuresFocal or non-focal dysfunction Usually causes encephalitis but not meningitis Sites- corticomedullary junction of cerebral hemispheres, basal ganglia, brainstem, pituitary Fever, headache, altered mental status and focal deficits Focal- seizures, hemiparesis, aphasia, visual field defects, cranial nerve palsies, movement disorders(choreoathetosis), ataxia Accompanying cerebral edema- confusion, lethargy, dementia, coma Hyponatremia, Panhypopituitarism DiagnosisCT/MRI- Multiple or occasionally single lesions (<2 cm) with ring enhancement and surrounding edema (DD- Tuberculoma, CNS lymphoma, fungal or bacterial abscess) CSF- Modest increase in protein and cell count, normal glucose, positive PCR Anti Toxoplasma antibody- if negative- chance of mass lesion being toxoplasma is <10% Therapeutic trial- Clinical improvement- by day 3- 50%, by day 7- 90%. Radiological resolution3weeks to 6 months Definitive diagnosis- brain biopsy- reserved for patients who have failed 2-4 weeks of empirical therapy TreatmentSulfadiazine and Pyrimethamine with leucovorin for minimum of 4-6 weeks

Alternative- Clindamycin+pyrimethamine, Atovaquone+pyrimethamine, Azithromycin+pyrimethamine+rifabutin PreventionPrimary- CD4<100, antibody positive- TMP/SMX Secondary- maintenance Rx with sulfadiazine+pyrimethamine+leucovorin till CD4>200 for 6 months Seronegative- minimize risk of infection- avoid consumption of undercooked meat, careful handwashing esp after contact with soil/handling cats

Progressive multifocal leukoencephalopathy Etiologic agent- JC virus Late manifestation- CD4<100 Seen in 1-4% of AIDS patients Regions involved- Cerebral hemispheres (subcortical white matter), brainstem, cerebellum Clinical featuresProtracted course Multifocal disease May have mental status changes Seizures, ataxia, hemiparesis, aphasia, sensory loss, visual field defects Headache, nausea, vomiting, fever- if present suggests alternate diagnosis DiagnosisMRI- Multiple, non-enhancing, white matter lesions, may coalesce. Predilection for occipital and parietal lobes. T2 hyperintense and T1 hypointense. CSF- JC virus DNA- 76% sensitivity and 100% specificity TreatmentNo specific Rx cART- Median survival before ART- 3-6 months, after ART- 2 years (upto 15 years). However only 50% show neurological improvement Antiviral agents- Cidofovir, Mefloquine, Mirtazapine, Cytarabine- no evidence from trials Prognostic factorsCD4 > 100 HIV viral load < 500

Cryptococcosis Leading infectious cause of meningitis in AIDS Can cause- meningitis, cryptococcomas Most due to C neoformans, 12% due to C gatti AIDS defining illness in 2% Occurs when CD4<100 Clinical featuresSubacute meningoencephalitis Fever, headache, nausea, vomiting, altered mental status, meningeal signs, lethargy Focal deficits, seizures unusual Cranial nerve involvement may occur (especially sudden catastrophic vision loss and hearing loss) Indolent- subacute dementia Cryptococcoma- present like SOL, more common with C gatti 1/3rd have associated pulmonary disease Others- Molluscum like skin lesions, lymphadenopathy, palatal and glossal ulcers, arthritis, gastroenteritis, myocarditis, prostatitis (prostate may serve as reservoir) ComplicationsMostly due to C gatti Raised ICP, Hydrocephalus Blindness and hearing loss Focal deficits and seizures DiagnosisMRI- Increased ICP, hydrocephalus, mass lesions CSF- elevated opening pressure, modest elevation in protein and WBC count and decrease in glucose, identify organism with India Ink or antigen test (CRAg) or culture. 25-30% have normal CSF

Blood culture often positive Cultures from other sites- urine and sputum CRAg in blood Brain biopsy for cryptococcoma TreatmentInduction, consolidation and maintenance Primary regimen- Amphotericin B 0.7mg/kg/day or Liposomal Amphotericin 4-6mg/kg/day plus Flucytosine 25mg/kg in 4 divided doses for 2 weeks followed by Fluconazole 400mg/day for 8 weeks followed by Fluconazole 200mg/day till CD4 count > 200 for 6 months in response to ART Other regimens- Instead of Flucytosine, can use Fluconazole 800 mg/day for first 2 weeks Repeated CSF removal (to reduce ICP) if patient has persistent headache- goal is to reduce CSF pressure to <20cm H2O Monitoring on RxSerum CRAg- not done routinely CSF culture 2 weeks after therapy (even if patients improve)- if positive- consider drug susceptibility testing and extend duration of therapy CSF pressure- Measure at time of 1st LP. Further measurements- Persistent clinical symptoms during induction(esp if baseline ICP elevated), if IRIS suspected, at 2 weeks after Rx. PrognosisPoor prognosis- Altered mental status, Positive India ink (indicating high fungal load), high CSF pressure, low glucose levels, low CSF cells (<20), extraneural infection, absence of antibody to capsular polysaccharide, CSF/Serum CRAg level > 1:32, PreventionPrimary- CD4<200- Fluconazole 200mg/day

CNS TB One of the most common infections. Can appear at any stage. Manifestations depend on stage of disease- at early stage, it resembles TB in non-HIV patients and at late stages, manifestations are atypical. Early stage- Lungs most commonly affected, typical features- cough, fever, respiratory signs, cavitation on CXR. Later stages- extrapulmonary more common and pulmonary disease resembles primary TB (minimal parenchymal lesions, lymph node enlargement, military pattern). Extrapulmonary TB in 40-60% of HIV patients. PathogenesisCNS TB forms- Meningitis, granulomas, abscess Isolated or part of disseminated/military TB In non-HIV infectedInfection acquired in droplet inhalation or ingestion f/b hematogenous dissemination Deposition of bacilli adjacent to subarachnoid space or ventricles If host immune response is adequate- granulomas form (Rich focus)- may be clinically silent or present as intracranial SOL In TBM- Rich focus ruptures into subarachnoid space, induces inflammation and exudate formation Hydrocephalus may develop- Communicating- Exudates around the arachnoid villi reduce CSF resorption , Obstructive- Exudates interrupt CSF flow through ventricles Stroke- Immune response triggers vasculitis in circle of Willis, vertebrobasilar system and MCA branches Cranial nerve involvement- Compression by exudates, ischemia due to vasculitis In HIV infectedIncreased risk of activation of latent infection Increased risk of rapid progression of primary disease without intervening period of latency Non-HIV- Individuals with latent infection have lifetime risk of 10-20% of developing TB

HIV- 10% annual risk Risk of TBM stronger in HIV+ patients who are IV drug users TBM Clinical courseFever, headache and vomiting Weight loss Altered level of sensorium more prominent in HIV+ Raised ICP features- papilledema, LR palsy Seizures Focal deficits- cranial nerve palsies, hemiplegia, paraplegia HIV+ more likely to have lymphadenopathy, hepatosplenomegaly and concomitant active pulmonary TB DiagnosisCT/MRIFindings include- Basal meningeal enhancement and exudates, Hydrocephalus, infarcts and tuberculomas CSFIncreased opening pressure, Clear or straw colored, Raised protein and WBC (lymphocytic), Low sugar (CSF/Serum RBS<0.5). Microbiological diagnosis- AFB stain, culture and PCR (variable sensitivity (0->80%) Atypical findings in HIV- Normal protein/WBC counts/Glucose, neutrophilic predominance Other investigationsLow sodium Anemia, Leucopenia CXR and USG abdomen to look for other sites of involvement

TreatmentMedicalATT for 9-12 months- Rifampicin may need to be replaced with Rifamycin/Rifabutin if Nevirapine/PI based ART regimen if used or alternatively Efavirenz regimen can be used along with Rifampicin Steroids- role in HIV+ patients controversial Correction of sodium, antiedema measures SurgicalFor hydrocephalus- shunt

ComplicationsHydrocephalus- Communicating or obstructive Stroke Cranial nerve palsies Optochiasmatic arachnoiditis- can cause blindness Hypothalamic-pituitary involvement- DI, other hormone deficiencies (GH) Spine- myelitis and spinal arachnoiditis- present with para/quadriparesis with bladder involvement. Can develop secondary syrinx Hyponatremia- SIADH or CSW syndrome